Project Summary/Abstract Complex biophysical cellular interactions are integral to many hematological processes ranging from platelet aggregation to leukocyte rolling and extravasation through the endothelium. While molecular biology has led to the discovery of numerous causative genes and associated biochemical signaling pathways, that is only part of the picture, analogous to knowing only the actors in a play without knowing the plot. To fully comprehend how these cellular machines in our blood work in concert in the dynamic environment of the circulation and how these physical interactions go awry during disease states requires physical tools that operate at the cellular and subcellular scales. With my background as a ?physician-scientist-engineer? trained in clinical hematology and bioengineering with specific focuses in micro/nanosystems technologies, microfluidics, and cellular mechanics, my laboratory has steadily merged these fields together to develop tools to answer biophysical hematologic questions that were previously technologically infeasible, which we then immediately translate to my patients' bedsides. With specific focuses on hematologic processes and diseases such as hemostasis, thrombosis and sickle cell disease, our laboratory has leveraged our unique combined clinical and engineering expertise to invent groundbreaking microtechnologies that either function as in vitro models of hematologic processes and disease that are more physiologically relevant than current systems or enable answering specific biophysical questions in hematology that current systems are incapable of. More specifically, we have developed: 1) ?organ-on-chip? technologies to enable vascularized microfluidic models of the microvasculature that function as physiologically relevant models of hemostasis, thrombosis, and sickle cell disease pathophysiology and 2) microengineered platforms to study the cellular mechanics of how platelets respond to their biophysical microenvironment. Collectively, our microtechnologies have not only led to groundbreaking research that have addressed questions in hematology that were not answerable with current assays, but also serve as drug discovery platforms, precursor technologies for novel diagnostic devices, and even paradigm-shifting drug delivery strategies. Moving forward, our research program progresses both in terms of technology development and application thereof, from asking basic impactful questions as well as translation towards the patient. Examples of the former involve incorporating more complex microengineered features into our microfluidics, such as mechanical components and novel biomaterials, to enable an ?endothelialized? bleeding model to study all of the principal components of hemostasis in vitro and a collagen hydrogel-based microvasculature-on-a-chip to investigate how cell-cell interactions in sickle cell disease causes endothelial dysfunction, respectively. On the other hand, we are also now applying our existing microtechnologies as biophysical biomarkers of hematologic diseases such as immune thrombocytopenia. Overall, our laboratory's unique ?basement-to-bench-to-bedside? approach will not only will impact hematology research, but most importantly, improve the lives of my patients.